Abstract

In neuroblastoma, mutations in the anaplastic lymphoma kinase (ALK) tyrosine kinase gene have been identified in 8-10 % of primary tumors. The most common and potent ALK mutation, ALKF1174L, leads to the constitutive activation of the ALK protein and is associated preferentially with MYCN amplification, a markedly poorer prognosis, and confers resistance to the promising ALK inhibitor crizotinib. The development of more efficacious ALK inhibitors will benefit from non-invasive imaging strategies for the rapid identification of children with high-risk ALK-expressing or mutated neuroblastoma.

Histological correlates revealed a significantly (p<0.05) higher uptake of the perfusion marker Hoechst 33342, and the presence of large hemorrhagic blood lakes filled with stagnant deoxygenated erythrocytes, in tumors within the TH-MYCN mice, but not the TH-ALKF1174L/TH-MYCN model. Together these corroborate the IS-MRI findings (relatively fast native R2* and significant ΔR2*, indicative of vascular instability, in tumors in the TH-MYCN mice).

IS-MRI provides a robust method to discriminate and identify TH-MYCN transgenic mice harboring the ALKF1174L mutation based on a stark differential vascular phenotype, which may impact on impaired drug delivery. IS-MRI is suitable for the scanning of young children, and quantitation of native R2* easily incorporated into existing pediatric clinical imaging protocols. This approach could provide a robust and rapid indicator of ALK genotypic status of the tumor, enabling the early identification of children with ultra high-risk neuroblastoma at the time of diagnosis.